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1.
PLoS One ; 10(2): e0118379, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25710492

RESUMO

Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aß peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aß peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aß levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genética , Fator Neurotrófico Derivado do Encéfalo/química , Butiratos/farmacologia , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocarbonetos Halogenados/farmacologia , Microscopia Confocal , Microscopia de Vídeo , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transporte Proteico/efeitos dos fármacos , Pontos Quânticos/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vesículas Sinápticas/metabolismo
2.
Biochemistry ; 53(4): 702-13, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24401146

RESUMO

Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid ß peptide variant (Aß42). In the majority of familial AD (FAD) cases, e.g., those harboring mutations in presenilin 1 (PS1), there is a relative increase in the levels of Aß42 compared to the levels of Aß40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole γ-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769-780] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255-1258]. Here we describe a series of GSMs with physicochemical properties improved compared to those of AGSMs. Specific heterocycle replacements of the phenyl rings in AGSMs provided potent molecules with improved aqueous solubilities. A number of these soluble γ-secretase modulators (SGSMs) potently lowered Aß42 levels without inhibiting proteolysis of Notch or causing accumulation of amyloid precursor protein carboxy-terminal fragments, even at concentrations approximately 1000-fold greater than their IC50 values for reducing Aß42 levels. The effects of one potent SGSM on Aß peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated Aß species. This SGSM also inhibited Aß42 peptide production in a highly purified reconstituted γ-secretase in vitro assay system and retained the ability to modulate γ-secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Fragmentos de Peptídeos/biossíntese , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Ensaios Enzimáticos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Mutação , Presenilina-1/genética , Presenilina-1/metabolismo , Proteólise , Receptor Notch1/metabolismo , Solubilidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
3.
Neuron ; 67(5): 769-80, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-20826309

RESUMO

Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Abeta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/imunologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Anticorpos/farmacologia , Butiratos/farmacologia , Caderinas/metabolismo , Células Cultivadas , Cricetinae , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Transferência Ressonante de Energia de Fluorescência/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrocarbonetos Halogenados/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Ratos , Receptores Notch/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Transfecção/métodos
4.
J Med Chem ; 46(22): 4702-13, 2003 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-14561090

RESUMO

Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.


Assuntos
Inibidores Enzimáticos/síntese química , Indóis/síntese química , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Indóis/química , Injeções Intravenosas , Proteína Quinase 14 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/química , Modelos Moleculares , Ligação Proteica , Isoformas de Proteínas , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese
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